Abstract This project seeks to advance controlled drug delivery systems via the development of novel mechanically activated microcapsules (MAMCs) for therapeutic delivery in response to mechanical load. While previous strategies have established microcapsules with various triggered release mechanisms (e.g., pH, heat, osmotic swelling) for drug delivery, most require external actuation, and physiological feedback plays little role in release. This proposal takes the unique approach of using mechanically loaded environments (e.g., articulating joints) to trigger and control release of therapeutics. Upon rupture, bioactive molecules released from microcapsules (embedded within matrices), can stimulate anabolic processes leading to cell proliferation, differentiation, matrix biosynthesis, or a host of other responses including control of inflammation. Given that the timing of release is controlled by mechanical load, it is possible to tune the release of factors based on the mechano-sensitivity of the microcapsules. For example, these MAMCs may be used in conjunction with engineered tissues to foster regeneration under controlled loading during rehabilitation, or designed to actuate in response to normal walking and exercise, so as to promote rapid local repair. In Aim 1 we will investigate the structure-release properties of the MAMCs under physiologic loading scenarios by modifying key fabrication parameters, including polymer composition, shell thickness-to-radius ratio, and shell elasticity/plasticity. In Aim 2 we will characterize failure properties of MAMCs embedded in engineered matrices analogous to native tissue as a function of fabrication parameters, adhesion to local environment, and load. In Aim 3 we will evaluate the effect of therapeutic release from MAMCs embedded within engineered cartilage for the purpose of stimulating growth in response to physiologic loading and promoting repair in response to injurious loading. Finally, in Aim 4, we will assess the actuation of MAMCs in an in vivo load bearing animal model of cartilage repair. Collectively these Aims will test the hypothesis that physiologically relevant mechanical forces can temporally and spatially control the delivery of bioactive growth promoting molecules that positively impact tissue formation and repair. Completion of these Aims will culminate with validation of MAMCs in a clinically relevant animal model and support this as a novel drug delivery system with broad applications in directing regeneration and repair in mechanically loaded tissues.